rs139548132

Variant names:

• chr1-119140608-A-C
• rs139548132
• NM_015836.4:c.37T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-119140608-A-C
• chr1-119140608-A-G
• chr1-119140608-A-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM5 PP5 BP4 BS1_Supporting BS2

The NM_015836.4(WARS2):​c.37T>G​(p.Trp13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,613,944 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W13R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (22 hom.)
• Consequence: WARS2 NM_015836.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16 U:4 B:2
• Conservation: PhyloP100: -0.145
• Publications: 23 publications found

Genes affected

WARS2 (HGNC:12730): (tryptophanyl tRNA synthetase 2, mitochondrial) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Two forms of tryptophanyl-tRNA synthetase exist, a cytoplasmic form, named WARS, and a mitochondrial form, named WARS2. This gene encodes the mitochondrial tryptophanyl-tRNA synthetase. Two alternative transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

WARS2-AS1 (HGNC:40612): (WARS2 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-119140608-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1947813.
• PP5: Variant 1-119140608-A-C is Pathogenic according to our data. Variant chr1-119140608-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 440915.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0043417513). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00315 (480/152394) while in subpopulation NFE AF = 0.00489 (333/68040). AF 95% confidence interval is 0.00446. There are 0 homozygotes in GnomAd4. There are 227 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 22 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015836.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS2	NM_015836.4	MANE Select	c.37T>G	p.Trp13Gly	missense	Exon 1 of 6	NP_056651.1	Q9UGM6-1
	WARS2	NM_001378228.1		c.37T>G	p.Trp13Gly	missense	Exon 1 of 6	NP_001365157.1	B7Z6G7
	WARS2	NM_001378229.1		c.37T>G	p.Trp13Gly	missense	Exon 1 of 5	NP_001365158.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS2	ENST00000235521.5	TSL:1 MANE Select	c.37T>G	p.Trp13Gly	missense	Exon 1 of 6	ENSP00000235521.4	Q9UGM6-1
	WARS2	ENST00000369426.9	TSL:1	c.37T>G	p.Trp13Gly	missense	Exon 1 of 6	ENSP00000358434.5	Q9UGM6-2
	WARS2-AS1	ENST00000425884.7	TSL:1	n.213A>C		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 480 AN: 152276 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00489

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00322 AC: 809 AN: 250992 AF XY: 0.00352

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.00357

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000695

Gnomad NFE exome AF: 0.00436

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.00363 AC: 5311 AN: 1461550 Hom.: 22 Cov.: 30 AF XY: 0.00372 AC XY: 2703 AN XY: 727072

African (AFR) AF: 0.000478 AC: 16 AN: 33468

American (AMR) AF: 0.00418 AC: 187 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00369 AC: 318 AN: 86218

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53380

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5766

European-Non Finnish (NFE) AF: 0.00398 AC: 4423 AN: 1111822

Other (OTH) AF: 0.00404 AC: 244 AN: 60386

GnomAD4 genome AF: 0.00315 AC: 480 AN: 152394 Hom.: 0 Cov.: 33 AF XY: 0.00305 AC XY: 227 AN XY: 74520

African (AFR) AF: 0.000841 AC: 35 AN: 41604

American (AMR) AF: 0.00418 AC: 64 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4832

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10632

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00489 AC: 333 AN: 68040

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00399 Hom.: 4

Bravo AF: 0.00300

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00331 AC: 402

EpiCase AF: 0.00616

EpiControl AF: 0.00510

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	1	-	Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (7)
3	2	-	Parkinsonism-dystonia 3, childhood-onset (5)
2	-	2	not provided (4)
3	-	-	WARS2-related disorder (3)
-	1	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental disorder (1)
1	-	-	Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures;C5676913:Parkinsonism-dystonia 3, childhood-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.14
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.12
Sift	Benign	0.081	T
Sift4G	Uncertain	0.016	D
Polyphen		0.0010	B
Vest4		0.43
MVP		0.25
MPC		0.74
ClinPred		0.037	T
GERP RS		0.72
PromoterAI		-0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.62
Mutation Taster		=87/13	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139548132; hg19: chr1-119683231; COSMIC: COSV99346234; COSMIC: COSV99346234;